Serum Concentrations Of Morphine Research Articles

Prospective Association of Serum Opioid Levels and Clinical Outcomes in Patients With Cancer Pain Treated With Intrathecal Opioid Therapy.

Opioids remain the mainstay of cancer pain management but are associated with systemic toxicity. In refractory cancer pain, intrathecal therapy (ITT) is associated with improved pain control, reduced systemic side effects, and improved survival. It has been assumed that ITT decreases systemic serum opioid levels and their associated toxicity, but there are limited data to support this assumption. This study hypothesizes that serum opioid levels decrease with ITT. Secondary objectives include comparative measures of pain, bowel function, and other cancer-related symptoms. Fifty-one cancer patients undergoing ITT for cancer pain were recruited in a prospective observational study. Daily oral morphine equivalency (OME) dose, serum opioid levels, Brief Pain Inventory (BPI), MD Anderson Symptom Inventory (MDASI), and a constipation questionnaire were obtained at the time of implant, and 4 and 8 weeks postoperatively. Average baseline daily OME was 375 mg (median, 240; interquartile range, 150-405; range, 0-3160), mean serum morphine concentration was 53.7 ng/mL (n = 17), and mean oxycodone concentration was 73.7 ng/mL (n = 20). At 4 weeks, 87.5% of patients had discontinued non-IT opioids, and 53% had undetectable (<2 ng/mL) serum opioid concentrations. At 8 weeks, 92% remained off all non-IT opioids and 59% had undetectable serum opioid levels. IT morphine doses >4.2 mg/d were invariably associated with detectable serum levels; with doses <4.2 mg, morphine was undetectable in 80% of subjects. IT hydromorphone doses >6.8 mg/d were detectable in the serum. Using linear mixed model analyses, there were statistically significant decreases in the mean "worst pain," "average pain," and MD Anderson symptom severity and interference scores at 4 and 8 weeks. This change was independent of serum opioid levels; when analyzed separately, there was no difference in the pain scores of subjects with detectable serum opioid levels compared to those with undetectable levels at 4 and 8 weeks. Constipation ranked as "quite a bit" or "very much" decreased from 58.7% to 19.2% of subjects at week 4 (P < .001) and to 37.5% at 8 weeks (P = .23). A very low complication rate was observed. ITT for cancer pain was associated with a marked reduction in serum opioid concentrations, with the majority of patients having undetectable serum levels. Reducing serum opioid concentrations in cancer patients may have implications with respect to restoring bowel function, improving fatigue, and promoting the integrity of antitumor immune function and warrants further study.

Ketamine and norketamine attenuate oxycodone tolerance markedly less than that of morphine: from behaviour to drug availability

BackgroundKetamine attenuates morphine tolerance by antagonising N-methyl-d-aspartate receptors. However, a pharmacokinetic interaction between morphine and ketamine has also been suggested. The interaction between oxycodone and ketamine is unclear. We studied the effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance focusing on both the pharmacodynamic and pharmacokinetic interactions. MethodsMorphine 9.6 mg day−1 or oxycodone 3.6 mg day−1 was delivered to Sprague–Dawley rats by subcutaneous pumps. Once tolerance had developed, the rats received subcutaneous injections of ketamine or norketamine. Tail-flick, hot-plate, and rotarod tests were performed. Drug concentrations were measured with high-performance liquid chromatography–tandem mass spectrometry. ResultsAnti-nociceptive tolerance to morphine and oxycodone developed similarly by Day 6. Acute ketamine 10 mg kg−1 and norketamine 30 mg kg−1 attenuated morphine tolerance for 120 and 150 min, respectively, whereas in oxycodone-tolerant rats the effect lasted only 60 min. Both ketamine and norketamine increased the brain and serum concentrations of morphine, and inhibited its metabolism to morphine-3-glucuronide, whereas oxycodone concentrations were not changed. Morphine, but not oxycodone, pretreatment increased the brain and serum concentrations of ketamine and norketamine. Ketamine, but not norketamine, significantly impaired the motor coordination. ConclusionsKetamine and norketamine attenuated morphine tolerance more effectively than oxycodone tolerance. Ketamine and norketamine increased morphine, but not oxycodone brain concentrations, which may partly explain this difference. Norketamine is effective in attenuating morphine tolerance with minor effects on motor coordination. These results warrant pharmacokinetic studies in patients who are co-treated with ketamine and opioids.

Oral morphine dosing predictions based on single dose in healthy children undergoing surgery.

Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose. The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens. Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg-1 , 200 mcg·kg-1 , 300 mcg·kg-1 ). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (TLAG ), and absorption half-time (TABS ). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg-1 ) at different dosing intervals (3, 4, 5, 6, 8, 12 h). The oral morphine formulation had F 0.298 (CV 36.5%), TLAG 0.45 (CV 63.6%) h and TABS 0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg-1 achieved a mean CMAX 10 mcg·l-1 . Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg·l-1 ; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l-1 at steady state. Oral morphine 200 mcg·kg-1 then 100 mcg·kg-1 4 h or 150 mcg·kg-1 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses.

Serum and urine concentrations of morphine and morphine metabolites in patients with advanced cancer receiving continuous intravenous morphine: an observational study

BackgroundThe feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This study aimed to determine what predicts serum concentrations of morphine in cancer patients receiving continuously intravenous morphine, the relationships between serum concentration of morphine/its metabolites and urinary concentrations, and the relation between morphine concentrations and with clinical outcomes.MethodsWe collected serum and urine samples from 24 patients with advanced cancer undergoing continuously intravenous morphine therapy. Serum samples were obtained at day one. Spot urine samples were collected once daily on three consecutive days. Pain and adverse drug events were assessed using the Korean version of MD Anderson Symptom Inventory.ResultsA total of 96 samples (72 urine and 24 serum samples) were collected. Median dose of morphine was 82.0 mg/24 h. In a multivariate analysis, total daily morphine dose was the most significant predictors of both serum and urine concentration of morphine. Morphine, M6G, and M3G in serum and urine were statistical significantly correlated (correlation coefficient = 0.81, 0.44, 0.56; p values < 0.01, 0.03, 0.01, respectively).ConclusionSpot urine concentrations of morphine and its metabolites were highly correlated to those of serum. Total dose of daily morphine was related to both serum and urine concentration of morphine and its metabolites.

Comparison of serum and lithium‐heparinate plasma for the accurate measurements of endogenous and exogenous morphine concentrations

Comparison of serum and lithium‐heparinate plasma for the accurate measurements of endogenous and exogenous morphine concentrations

Oral-Parenteral Conversion Factor for Morphine in Palliative Cancer Care: A Prospective Randomized Crossover Pilot Study

Objective. This pilot study clinically tests whether a conversion factor of 2 to 1 is appropriate when changing from oral to parenteral morphine administration in the treatment of cancer-related nociceptive pain and calculates the size of an adequately powered future study. Methods. Eleven outpatients with incurable cancer and well-controlled nociceptive pain were randomly assigned to either intravenous or subcutaneous morphine using half the previous oral 24-hour dose. Each group crossed over after the first three-day period. Serum concentrations of morphine and its metabolites were monitored as well as intensity of pain. Results. Oral to subcutaneous and oral to intravenous quotas of morphine concentrations were approximately 0.9. Subcutaneous to intravenous morphine quotas were 1. Conclusions. The conversion factor of 2 to 1 seems to be a reasonable average but with an obvious need for individual adjustments. Concurrent medications and substantially higher doses of morphine could potentially affect the appropriate conversion factor. An adequately powered study to validate these findings would need at least 121 patients.

Baby boy blue – why is this newborn lethargic?

Aone-week-old boy was seen in the emergency department with a two-day history of poor feeding and increasing lethargy. He was born at term after an uneventful pregnancy by repeat caesarean section. His birth weight was 3.2 kg. The patient’s Apgar scores were 8 and 9, and he was discharged home on day 3 with exclusive breastfeeding. He has two older siblings: a five-year-old sister born in the mother’s homeland of Sri Lanka, and a three-year-old brother born in Canada by caesarean section because of failure to progress. Both siblings and the parents are in good health, and there was no significant family history. On examination, the baby was a term male infant, afebrile with a blood pressure of 75/45 mmHg, heart rate of 120 beats/ min and shallow respirations with a rate of 16 breaths/min. He did not respond well to stimuli and had a poor suck. His physical examination was otherwise unremarkable. A full septic workup was performed, with unremarkable results. During the process of the workup, a urine drug screen was sent, which was positive for opiates. More specific analysis revealed a serum morphine concentration of 55 µg/mL – a potentially toxic concentration. A 0.01 mg/kg dose of naloxone was administered, with good clinical improvement. Further questioning revealed that the mother was given an acetaminophen-codeine product for analgesia postcaesarean section. She had been having increasing pain after discharge because she was caring for her newborn plus two busy older siblings. She reported taking one or two pain tablets three or four times a day, and noted excellent pain relief but also drowsiness and constipation. Genetic testing was performed to investigate the maternal and infant pathways of codeine and morphine metabolism. The mother was shown to have a gene duplication for cytochrome P450 2D6 (CYP2D6), which classified her as an ultrarapid metabolizer. The mother was also found to be homozygous for the UGT 2B7*2 allele, a polymorphism in the glucuronidation of morphine associated with increased production of morphine 6-glucuronide, the active metabolite of morphine. This ‘two-hit’ genetic variation would expose her newborn to very high concentrations of morphine and the active metabolite of morphine via breast milk.

Pharmacokinetics of intra-articular morphine in horses with lipopolysaccharide-induced synovitis

ObjectiveTo describe the pharmacokinetics of intra-articularly (IA) administered morphine. Study designExperimental randomized, cross-over study. AnimalsEight adult healthy mixed breed horses aged 6.5 ± 2.3 (mean ± SD) years and weighing 535 ± 86 kg. MethodsUnilateral radiocarpal synovitis was induced by IA injection of 3 μg lipopolysaccharide (LPS) on two occasions (right and left radiocarpal joint, respectively) separated by a 3-week wash-out period. Treatments were administered 4 hours post-LPS-injection: Treatment IA; preservative free morphine IA (0.05 mg kg−1) plus saline intravenous (IV) and treatment IV; saline IA plus preservative free morphine IV (0.05 mg kg−1). Concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide (M6G) were determined repeatedly in serum and synovial fluid (SF) by high-performance liquid chromatography mass spectrometry, at 2 and 4 hours and then at 4 hours intervals until 28 hours post-treatment. ResultsInjection of LPS elicited a marked and comparable synovitis in all LPS-injected radiocarpal joints. IA administered morphine was detectable in SF of all eight joints 24 hours post-treatment and in 6/8 joints 28 hours post-treatment. The terminal half-life of morphine in SF was estimated to be 2.6 hours. IA administration of morphine resulted in mean serum concentrations of morphine below 5 ng mL−1 from 2 to 28 hours after treatment. Conclusions and clinical relevanceIntra-articularly administered morphine remained within the joint for at least 24 hours. At the same time only very low serum concentrations of morphine and M6G were detected. The present results suggest that IA morphine at 0.05 mg kg−1 may be used for IA analgesia lasting at least 24 hours and give strong support to the theory that previously observed analgesic and anti-inflammatory effects of IA morphine in horses are most likely to be mediated peripherally.

Endogenous Morphine Levels Are Increased in Sepsis: A Partial Implication of Neutrophils

BackgroundMammalian cells synthesize morphine and the respective biosynthetic pathway has been elucidated. Human neutrophils release this alkaloid into the media after exposure to morphine precursors. However, the exact role of endogenous morphine in inflammatory processes remains unclear. We postulate that morphine is released during infection and can be determined in the serum of patients with severe infection such as sepsis.MethodologyThe presence and subcellular immunolocalization of endogenous morphine was investigated by ELISA, mass spectrometry analysis and laser confocal microscopy. Neutrophils were activated with Interleukin-8 (IL-8) or lipopolysaccharide (LPS). Morphine secretion was determined by a morphine-specific ELISA. μ opioid receptor expression was assessed with flow cytometry. Serum morphine concentrations of septic patients were determined with a morphine-specific ELISA and morphine identity was confirmed in human neutrophils and serum of septic patients by mass spectrometry analysis. The effects of the concentration of morphine found in serum of septic patients on LPS-induced release of IL-8 by human neutrophils were tested.Principal FindingsWe confirmed the presence of morphine in human neutrophil extracts and showed its colocalisation with lactoferrin within the secondary granules of neutrophils. Morphine secretion was quantified in the supernatant of activated human polymorphonuclear neutrophils in the presence and absence of Ca2+. LPS and IL-8 were able to induce a significant release of morphine only in presence of Ca2+. LPS treatment increased μ opioid receptor expression on neutrophils. Low concentration of morphine (8 nM) significantly inhibited the release of IL-8 from neutrophils when coincubated with LPS. This effect was reversed by naloxone. Patients with sepsis, severe sepsis and septic shock had significant higher circulating morphine levels compared to patients with systemic inflammatory response syndrome and healthy controls. Mass spectrometry analysis showed that endogenous morphine from serum of patient with sepsis was identical to poppy-derived morphine.ConclusionsOur results indicate that morphine concentrations are increased significantly in the serum of patients with systemic infection and that morphine is, at least in part, secreted from neutrophils during sepsis. Morphine concentrations equivalent to those found in the serum of septic patients significantly inhibited LPS-induced IL-8 secretion in neutrophils.

A randomized study of the serum pharmacokinetics of lower thoracic extended-release epidural morphine (DepoDur®) after lidocaine-epinephrine test dose administration in patients undergoing upper abdominal surgery

The primary objective was to evaluate the serum pharmacokinetic profile of a single 15-mg dose of extended-release epidural morphine (EREM) administered at the lower thoracic epidural space alone or following a lidocaine-epinephrine test dose in patients undergoing major upper abdominal surgery. This randomized, open-label study recruited men and women > or = 18 years of age scheduled for major upper abdominal surgery. Patients were randomly assigned to 1 of 5 treatment groups and were administered a single 15-mg dose of EREM or EREM preceded by a 3 ml lidocaine (1.5%)/epinephrine (1 : 200,000) test dose with or without a saline flush: EREM alone; test dose + flush + 3-minute wait + EREM; test dose + flush + 10-minute wait + EREM; test dose + flush + 15-minute wait + EREM; or test dose + 3-minute wait + EREM. EREM was administered at the lower thoracic epidural intervertebral space (T8 - T12) approximately 30 minutes before the surgical incision. Noncompartmental pharmacokinetic parameters were determined based on the serum concentration-time profiles of morphine and morphine metabolites. Effectiveness and safety were also assessed. The intent-to-treat and safety populations included 39 patients; the pharmacokinetic population included 37 patients. Administration of EREM 3 minutes after a lidocaine-epinephrine test dose, with or without a flush, resulted in an increased mean maximum serum concentration of morphine (Cmax; flush, 30.2 +/- 8.5 ng/ml; no flush, 25.6 +/- 10.1 ng/ml; EREM alone, 11.5 +/- 7.3 ng/ml) and a decreased median time to Cmax (tmax; flush, 0.2 h; no flush, 0.2 h; EREM alone, 2.0 h) compared with administration of EREM alone, without affecting relative morphine bioavailability. Flushing the catheter and waiting 15 minutes normalized the Cmax (11.4 +/- 6.4 ng/ml) but not the median tmax (0.5 h). There were no significant group differences in safety, tolerability, or analgesic effectiveness. The interaction between EREM and a lidocaine-epinephrine test dose administered at T8 - T12 can be minimized by waiting 15 minutes after test dose administration. The overall safety and effectiveness of 15 mg EREM administered at the lower thoracic epidural intervertebral space in patients undergoing major upper abdominal surgery appears similar to that observed in previous studies assessing lumbar administration. ClinicalTrials.gov Identifier: NCT00728832.

Pharmacokinetics of extended-release epidural morphine sulfate: Pooled analysis of six clinical studies

A pooled analysis of six clinical studies was conducted to describe the pharmacokinetics of extended-release epidural morphine sulfate. Data from six clinical studies evaluating extended-release epidural morphine sulfate in volunteers and abdominal or hip surgery patients were pooled and analyzed. Participants age 18 years or older received extended-release epidural morphine sulfate (2.5-40 mg) within 30 minutes of surgery initiation. Most participants received a test dose of 1.5% lidocaine with 1:200,000 epinephrine for epidural space identification 15 minutes before study drug administration. Blood samples were generally collected at 0.5, 2, 4, 8, 12, 18, 24, and 48 hours postinjection. Standard epidural morphine sulfate exhibited a spike in drug release, producing higher peak concentrations (C(max)) than 5-mg extended-release epidural morphine sulfate, which produced more prolonged serum morphine concentrations. Using labeled doses of extended-release epidural morphine sulfate (10-20 mg), the C(max) was comparable to that for 5-mg standard epidural morphine sulfate, whereas the apparent terminal elimination half-life and area under the serum concentration-time curve were twofold to fourfold greater and consistent with dose-proportional exposure. The mean dose-normalized C(max) for extended-release epidural morphine sulfate was 25% higher for women versus men. Administering extended-release epidural morphine sulfate 15 minutes after the test dose mitigated any pharmacokinetic interaction. Extended-release epidural morphine sulfate demonstrated dose- related reductions in postoperative fentanyl consumption and pain intensity. A pooled analysis of six studies revealed that extended-release epidural morphine sulfate provided a more prolonged release of morphine compared with standard epidural morphine sulfate. Extended-release epidural morphine sulfate displayed a consistent pharmacokinetic profile among adults, with only slight variability between men and women in C(max), which appeared to be mainly caused by differences in body weight.

Pharmacokinetic and pharmacodynamic study of morphine and morphine 6‐glucuronide after oral and intravenous administration of morphine in children with cancer

The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of morphine and morphine 6-glucuronide (M6G) in children with cancer. Serum concentrations of morphine and M6G in children who received single oral or short term continuous intravenous morphine were determined by HPLC and ELISA assays, respectively. The serum C(max) of morphine and M6G after i.v. morphine administration was 560.5 and 309.0 nM and the T(max) was 61 and 65 min, respectively. The elimination half-life was 140.0 and 328.7 min, respectively. After oral administration of morphine, the serum C(max) of morphine and M6G was 408.34 and 256.3 nM and the T(max) was 40.0 and 60 min, respectively. The half-life was 131.0 and 325.8 min, respectively. The side effects were: drowsiness (100%), nausea and/or vomiting (57%), pruritus (28%) and urinary retention (14%). There were no reports of respiratory complications. This study showed that pharmacokinetics factors of morphine and M6G in children were significantly different from adults. Therefore the required dose for children should be different from that of adults and should be based on studies performed on children rather than on studies on adults. Some adverse effects, particularly nausea and pruritus, may be commoner than is usually thought, while others, particularly respiratory problems did not occur.

Effect of morphine on the bispectral index during isoflurane anesthesia in dogs

ObjectiveTo assess the effect of morphine on the bispectral index (BIS) in dogs during isoflurane anesthesia maintained at a constant end–tidal concentration. Study designProspective, randomized, experimental trial. AnimalsEight adult Beagle dogs, weighing between 7.1 and 9.8 kg. MethodsAnesthesia was induced with isoflurane via a face mask. Dog's tracheas were intubated and anesthesia maintained with isoflurane at a constant end–tidal concentration (e′Iso) of 1.81% for a 30–minute equilibration period. Pulmonary ventilation was controlled to normocapnia. After equilibration, baseline values were recorded prior to intravenous administration of morphine sulfate (0.5 mg kg−1) (MT) or an equal volume of saline (CT). Measurements for heart rate, systolic, diastolic and mean arterial pressure (SAP, DAP and MAP) were recorded at 10, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after treatment. Bispectral index was recorded every 10 seconds for 3 minutes for each time measurement. Venous blood samples were collected at baseline, 10, 20, 30, 45, 60 and 120 minutes for determination of morphine serum concentrations. Anesthesia was discontinued after the last measurement and dogs were allowed to recover. ResultsBaseline BIS for MT and CT at 1.81%e′Iso were 63 ± 10 and 58 ± 9, respectively. Bispectral index in MT was 4–8% lower at 20, 75, 90 and 105 minutes compared with CT. There were no differences in BIS between baseline and any subsequent measurement within either MT or CT. Heart rate, SAP, MAP, and DAP decreased after morphine administration. Conclusion and clinical relevanceIntravenous administration of 0.5 mg kg−1 morphine sulfate did not cause clinically significant changes in the BIS of unstimulated dogs during isoflurane anesthesia at an e′Iso of 1.81%.

ANTINOCICEPTION VERSUS SERUM CONCENTRATION RELATIONSHIPS FOLLOWING ACUTE ADMINISTRATION OF INTRAVENOUS MORPHINE IN MALE AND FEMALE SPRAGUE‐DAWLEY RATS: DIFFERENCES BETWEEN THE TAIL FLICK AND HOT PLATE NOCICEPTIVE TESTS

1. Antinociception versus serum morphine concentration relationships were defined in male and female Sprague-Dawley rats administered single intravenous (i.v.) bolus doses of morphine, using the hot plate (2.1-14 mg/kg) and tail flick tests (1-8 mg/kg). 2. Serum concentrations of morphine and morphine-3-glucuronide (M3G), its major metabolite in the rat, were assayed using high-performance liquid chromatography (HPLC) with electrochemical detection. 3. Significantly higher (P < 0.05) values of peak antinociception (approximately 1.7-fold), as well as the extent and duration of antinociception (approximately fourfold), were observed in male compared with female rats administered 10 mg/kg morphine in the hot plate test. Although there were no significant sex-related differences in the area under the serum morphine concentration versus time curve (AUC) at this dose, systemic exposure to M3G (M3G AUC) was significantly higher (approximately twofold; P < 0.05) in female than male rats. 4. In contrast with most previous studies investigating sex differences in morphine antinociception in rats, the antinociceptive effects of single i.v. doses of morphine (1-8 mg/kg) in the tail flick test did not differ significantly between male and female rats. 5. Morphine ED(50) and EC(50) values (95% confidence intervals) for antinociception in the hot plate test were significantly lower (P < 0.05) in male rats (ED(50) 8.4 mg/kg (7.6-9.2); EC(50) 1.8 nmol/L (1.5-2.1)) compared with female rats (ED(50) 10.6 mg/kg (9.1-12.0); EC(50) 3.7 nmol/L (3.4-4.1)). However, in the tail flick test, there was no significant difference between male and female rats in ED(50) (1.8 (0.4-3.3) and 1.4 mg/kg (0.4-2.5), respectively) or EC(50) (0.5 (0.3-0.6) and 0.4 nmol/L (0.2-0.5), respectively) values. 6. Supraspinal attenuation of morphine antinociception by M3G may account for these differences.

Elevated Morphine Concentrations in Neonates Treated With Morphine and Prolonged Hypothermia for Hypoxic Ischemic Encephalopathy

Asphyxia and hypothermia may modify drug pharmacokinetics. We investigated whether analgesia with morphine in neonates with hypoxic ischemic encephalopathy undergoing prolonged moderate systemic hypothermia resulted in elevated serum morphine concentrations compared with normothermic infants. Infants from 1 center participating in a multicenter randomized study of moderate whole-body hypothermia after perinatal asphyxia (the Total Body Hypothermia Study) were randomly selected for treatment with hypothermia (n = 10) or for standard care on normothermia (n = 6). Hypothermia (33 degrees C to 34 degrees C) was started before 6 hours of age and maintained for 72 hours. All of the infants were treated with a continuous infusion of morphine-hydrochloride, with the rate adjusted according to clinical status. Serum morphine concentrations were determined at 6, 12, 24, 48, and 72 hours after birth. Serum morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng/mL (137-767 ng/mL) in the hypothermia-treated infants and 206 ng/mL (88-327 ng/mL) in the infants on normothermia, despite similar morphine infusion rates and cumulative doses. Morphine concentrations correlated with morphine infusion rate, cumulative dose, and treatment with hypothermia. Serum morphine concentrations reached a steady state after 24 hours in the normothermic infants but continued to increase throughout the assessment period in the hypothermia group. Morphine clearance was low in both groups: (median [range]) morphine clearance estimated from area under the curve was 0.69 mL/min per kg (0.58-1.21 mL/min per kg) in hypothermic group and 0.89 mL/min per kg (0.65-1.33 mL/min per kg) in infants on normothermia. Serum morphine concentrations >300 nL/mL occurred more often in the hypothermia group and when the morphine infusion rate was >10 microg/kg per h. Infants with hypoxic ischemic encephalopathy have reduced morphine clearance and elevated serum morphine concentrations when morphine infusion rates are based on clinical state. Potentially toxic serum concentrations of morphine may occur with moderate hypothermia and infusion rates >10 microg/kg per h.

Genetic variation and response to morphine in cancer patients

Pain is a common symptom for patients with cancer, and opioids are the treatment of choice for moderate or severe cancer-related pain. Central side effects, such as drowsiness, confusion, and hallucinations, can limit the use of opioids in clinical practice. The authors prospectively recruited 228 cancer patients who received morphine. Clinical data, including pain and side-effect scores, were correlated with genotype data. Genetic variation in the multidrug resistance-1 gene (MDR-1) was associated with moderate or severe drowsiness and confusion or hallucinations. Patients who carried the common guanosine (G) allele at position 2677 in exon 26 were less likely to experience drowsiness and confusion or hallucinations than patients who carried the variant thymidine or adenosine alleles, which code for alternate amino-acid substitutions (chi-square statistic, 13.3; P=.0003). In addition, genetic variation in the catechol-O-methyltansferase (COMT) enzyme was associated independently with these central side effects. Single nucleotide polymorphisms (SNPs) in intron 1 were associated significantly with central side effects; the most significant was at position -4873G (chi-square statistic, 9.1; P=.003). SNPs in intron 1, defined as haplotype, were present in 10.4% of the population and were associated significantly with central side effects (chi-square statistic, 7.7; P=.005). Genotype data did not correlate with morphine dose or serum morphine or metabolite concentrations in this study. COMT and MDR-1 genotypes were correlated with morphine-related central side effects. The authors believe that this work adds significantly to the current understanding of genetic variants that may influence an individual's response to opioids.

Einfluss von Änderungen der Opioidtagesdosis auf fahrrelevante kognitive und psychomotorische Leistungen

It has been shown that long-term treatment with opioids does not necessarily impair driving ability in patients suffering from chronic pain. However, few studies are so far available on how increases in daily opioid dosage affect driving ability. A prospective trial was conducted in patients suffering from chronic noncancer pain, to examine the effects of the daily dose of opioids on psychomotor and cognitive functions. A computerized test system was administered to patients before and 7 days after alteration of their opioid therapy, to determine performance affecting driving ability at each time point. The test design was based on both international and national recommendations for the examination of driving safety. Raising the daily dose of opioids and/or changing to an opioid at a higher WHO level had no effect on the functions relevant to driving ability in the group context. Pain intensity and serum concentrations of morphine influenced only few items in the test battery. Seven days after an increase in the daily dose of an opioid or after the initiation of opioid therapy there was no general deterioration in patients' driving ability at group level.

Long term methadone for chronic pain: A pilot study of pharmacokinetic aspects

Methadone is used as an alternative opioid when first line opioids fail to provide adequate pain control. Highly variable morphine:methadone dose ratios make switching challenging and little is known about the pharmacokinetics of long lasting methadone treatment for pain. Twelve patients treated with morphine for chronic non-malignant pain were switched to methadone. Seven of these patients continued with methadone throughout the nine months study period and only minor dose adjustments were performed. Serum concentrations of morphine, methadone and their metabolites were measured at baseline, day one and two, after dose titration and one week, five weeks, three months and nine months after the end of dose titration. Serum concentrations of methadone and its metabolite EDDP did not change significantly from the end of dose titration and during the nine months (repeated measures ANOVA: p = 0.88 and p = 0.06). Very low correlation between dose ratios and serum concentration ratios between morphine and methadone was observed. Large interindividual differences in serum concentrations and metabolism were observed. Our findings contradict that autoinduction of methadone metabolism takes place during long term treatment and supports that a 3-day opioid switch from morphine to methadone followed by a one week titration seems pharmacologically sound.

Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother

In April, 2005, a full-term healthy male infant, delivered vaginally, showed intermittent periods of diffi culty in breastfeeding and lethargy starting on day 7. During a well-baby paediatric visit on day 11, the paediatrician noted that the baby had regained his birthweight. On day 12, however, he had grey skin and his milk intake had fallen. He was found dead on day 13. Postmortem analysis showed no anatomical anomalies. Blood concentration of morphine (the active metabolite of codeine) was 70 ng/mL by gas chromatography-mass spectrometry (GC-MS)— neonates breastfed by mothers receiving codeine typically have morphine serum concentrations of 0–2·2 ng/mL. The mother had been prescribed a combination preparation of codeine 30 mg and paracetamol 500 mg after birth for episiotomy pain (initially two tablets every 12 h, reduced to half that dose from day 2 because of somnolence and constipation). She continued the tablets for 2 weeks. Because of poor neonatal feeding, she stored milk on day 10, which was later assayed for morphine by GC-MS. A morphine concentration of 87 ng/mL was found—the typical range of milk concentrations after repeated maternal codeine is 1·9–20·5 ng/mL at doses of 60 mg every 6 h. Genotype analysis was done for cytochrome P450 2D6 (CYP2D6), the enzyme catalysing the O-demethylation of codeine to morphine. The mother was heterozygous for a CYP2D6*2A allele with CYP2D6*2×2 gene duplication, classifi ed as an ultra-rapid metaboliser. This genotype leads to increased formation of morphine from codeine, consistent with the somnolence and constipation she experienced. The maternal grandfather, the father, and the infant had two functional CYP2D6 alleles (CYP2D6*1/ *2 genotypes), classifi ed as extensive metabolisers. The maternal grandmother was an ultra-rapid metaboliser. The clinical and laboratory picture is consistent with opioid toxicity leading to neonatal death. Most of the analgesic and central-nervous-system depressant eff ects of codeine are secondary to its metabolism to morphine by CYP2D6. Neonates invariably have impaired capacity to metabolise and eliminate morphine. Codeine is a commonly used analgesic after labour for pain associated with episiotomy and caesarean section. The American Academy of Pediatrics lists codeine as compatible with breastfeeding, despite lack of suffi cient published data to support this recommendation. This case shows that polymorphism of CYP2D6 can be life threatening for some breastfed babies. Given that the frequency of CYP2D6 ultra-rapid metaboliser genotypes ranges from 1% in Finland and Denmark to 10% in Greece and Portugal, and 29% in Ethiopia, this polymorphism is clinically important. Several strategies can be considered to prevent life-threatening neonatal toxicity (table). Careful follow-up of breastfeeding mothers using codeine, and their infants, may be a useful approach. Testing of mother–child pairs when the mother or neonate is experiencing symptoms consistent with opioid toxicity may be necessary—eg somnolence, or poor milk intake. The facilities to measure morphine concentrations are not routine in most hospitals; in any suspicious case, naloxone can reverse, and, therefore, corroborate opioid toxicity. Above all, avoidance of codeine use during breastfeeding, with its use being retained as second or third line for uncontrolled pain, could also avert this situation. Whatever clinical approach is taken, codeine cannot be considered as a safe drug for all infants during breastfeeding.

Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers in Hospice Patients With Cancer Pain

Racemic methadone is increasingly used to manage cancer pain. The authors studied 13 terminally ill patients with cancer pain, who underwent switching (rotation) from morphine to methadone. The relationship between initial morphine dose and final methadone dose, the pharmacokinetics of R- and S- methadone, and the degree of pain control and side effects were investigated. Preswitching serum morphine concentrations and second daily plasma concentrations of methadone were measured. The brief pain inventory (BPI) was used to assess pain every second day. "Worst pain" as measured by the BPI improved by >/=20% in 6 of the 13 patients. The mean morphine to methadone conversion ratio was 5.2 with wide interpatient variability (range 1.3 to 11). Average steady-state concentrations were 197 (98 to 379) mug/L and 272 (55 to 378) mug/L for R- and S-methadone, respectively. Mean population pharmacokinetic parameters for a 1-compartment model were 455 L and 338 L for apparent volume of distribution and 53.3 hours and 31.5 hours for half-life for R- and S- methadone, respectively. Bayesian estimates of apparent oral clearance for individual patients were 0.082 (0.052 to 0.112) L/kg/h and 0.117 (0.061 to 0.173) L/kg/h for R- and S- methadone, respectively (mean and 95% confidence interval). The low and variable clearance values generally resulted in slow achievement of steady-state concentrations over several days; inappropriately high plasma methadone levels occurred in 1 patient. Whereas optimal pain control was achieved in 46% of patients, there was no relationship with plasma concentrations of methadone. Best practice for methadone use in this patient group should include monitoring of both pain and methadone concentration.